17-42478584-G-C

Position:

• chr17-42478584-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001130021.3(ATP6V0A1):​c.628G>C​(p.Val210Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP6V0A1 NM_001130021.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

Genes affected

ATP6V0A1 (HGNC:865): (ATPase H+ transporting V0 subunit a1) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c", and d. Additional isoforms of many of the V1 and V0 subunit proteins are encoded by multiple genes or alternatively spliced transcript variants. This gene encodes one of three A subunit proteins and the encoded protein is associated with clathrin-coated vesicles. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ATP6V0A1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP6V0A1. . Gene score misZ 3.7439 (greater than the threshold 3.09). Trascript score misZ 4.4308 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with epilepsy and brain atrophy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy 104.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A1	NM_001130021.3	c.628G>C	p.Val210Leu	missense_variant	7/22	ENST00000343619.9	NP_001123493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A1	ENST00000343619.9	c.628G>C	p.Val210Leu	missense_variant	7/22	1	NM_001130021.3	ENSP00000342951.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 104;C5774184:Neurodevelopmental disorder with epilepsy and brain atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Goettingen

Oct 22, 2024

The variant c.649G>C (p.(Val217Leu)) in exon 7 of the ATP6V0A1-gene is not found in the gnomAD database, it affects a a weakly conserved nucleotide and a moderately conserved amino acid. There is a small physicochemical difference between Val and Leu. Missense variants are a known mechanism of disease based on Z-score of 4.44 (gnomAD v.4.1.0). ACMG criteria used for classification: PM2_sup, PP2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;T;.;.;D;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.0	M;.;.;.;M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N;N;.;N;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.25	T;T;T;.;T;.;.
Sift4G	Benign	0.29	T;T;T;T;T;T;T
Polyphen		0.30	B;B;.;B;B;.;.
Vest4		0.30
MutPred		0.47		Loss of loop (P = 0.0112);.;.;.;Loss of loop (P = 0.0112);.;.;
MVP		0.24
MPC		0.89
ClinPred		0.86	D
GERP RS		5.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.18
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40630602;